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REVIEWS

A clinicopathological classification of
granulomatous disorders
D Geraint James

Abstract Granulomatous disorders comprise a large

Granulomatous disorders comprise a family sharing the common histological de-
large family sharing the histological de- nominator of granuloma formation. Granulo-
nominator of granuloma formation. A mas may be confluent or discrete; the degree of
granuloma is a focal compact collection of necrosis is variable; the cell components diVer;
inflammatory cells, mononuclear cells and the presence or absence of Schaumann
predominating, usually as a result of the bodies and of calcification are distinctive. A
persistence of a non-degradable product clinicopathological synthesis provides the most
and of active cell mediated hypersensitiv- secure foundation.
ity. There is a complex interplay between
invading organism or prolonged antige- Granuloma formation
naemia, macrophage activity, a Th1 cell A granuloma is a focal, compact collection of
response, B cell overactivity and a vast inflammatory cells, mononuclear cells pre-
array of biological mediators. DiVerential dominating; it is usually formed as a result of
diagnosis and management demand a the persistence of a non-degradable product of
Royal Free Hospital active hypersensitivity. The granuloma is the
skilful interpretation of clinical findings
School of Medicine, end result of a complex interplay between
University of London,
and pathological evidence. They are clas-
invading organism or antigen, chemical, drug
Rowland Hill Street, sified into infections, vasculitis, immuno-
or other irritant, prolonged antigenaemia,
London NW3 2PF, UK logical aberration, leucocyte oxidase
macrophage activity, a Th1 cell response, B cell
deficiency, hypersensitivity, chemicals, overactivity, circulating immune complexes,
Correspondence to:
Professor James
and neoplasia. and a vast array of biological mediators (fig 1).
(Postgrad Med J 2000;76:457–465)
Areas of inflammation or immunological reac-
Submitted 7 July 1999
Accepted 22 November 1999 Keywords: granuloma; Th1 cell; cytokines; neoplasia tivity attract monocyte macrophages which
may fuse to form multinucleated giant cells,
and a transformation of macrophages to
Antigens epithelioid cells. The granuloma is an active
site of numerous enzymes and cytokines, and,
with aging, fibronectin and numerous progres-
Macrophage CD4 sion factors. There is a close relationship
MHC class II ThO between activated macrophages bearing in-
Molecules Lymphocyte
creased expression of major histocompatibility
complex (MHC) class II molecules and CD4+
Th1 lymphocytes. These T helper cells recog-
IL-6 Costimulator nise protein peptides presented to them by
IL-12 IL-4 CD28
antigen presenting cells bearing MHC class II
molecules. The T cell induces interleukin-1 on
the macrophage and thereafter a cavalcade of
Th1 Th2 chemotactic factors promote granulomagen-
esis. Interferon gamma (IFN-ã) increases the
expression of MHC class II molecules on mac-
Activated IL-2 IL-4 rophages, and activated macrophage receptors
B cells IFN-γ IL-5
TNF IL-10 carry an Fc fraction of IgG to potentiate their
ability to phagocytose. The end result is the
Plasma epithelioid granuloma which progresses under
cells Exuberant Anergy
hypersensitivity, the impact of transforming—and platelet—
cell mediated IL-4 derived growth factor towards fibrosis.1–3
Fibrosis immunity Fibroblast T cell activation also requires the B7:CD28/
CTLA:4 costimulatory pathway. With CD28
Macrophage Primed Th1 cells mediated costimulator, there is active T cell
Fibrosis proliferation; without it, there is ignorance,
Chemokines anergy, and apoptosis.4 Overstimulation of Th1
relative to Th2 cells leads to pronounced cell
Granuloma mediated hyperactivity, tissue destruction, and
Figure 1 The cytokine network (IFN-ã = interferon gamma; IL = interleukin; MHC = granuloma formation. This is slowed down by
major histocompatibility complex; TNF = tumour necrosis factor). B7–1 or B7–2 antagonists. The opposite occurs

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458 James

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Table 1 Classification of granulomatous disorders

(1) Infections (2) Vasculitis (5) Hypersensitivity Pneumonitis

Fungi Wegener’s Farmers’ lung
Histoplasma Necrotising sarcoidal Bird fanciers’
Coccidioides Churg-Strauss Mushroom workers’
Blastomyces Lymphomatoid Suberosis (cork dust)
Sporothrix Polyarteritis nodosa Bagassosis
Aspergillus Bronchocentric Maple bark strippers’
Cryptococcus Giant cell arteritis Paprika splitters’
Protozoa Systemic lupus erythematosus CoVee bean
Toxoplasma Spatlese lung
Leishmania (3) Immunological aberrations
Metazoa Sarcoidosis (6) Chemicals
Toxoplasma Crohn’s disease Beryllium
Schistosoma Primary biliary cirrhosis Zirconium
Spirochaetes Hepatic granulomatous disease Silica
T pallidum Langerhan’s granulomatosis Starch
T carateum Orofacial granulomatosis Talc
T pertenue Peyronie’s disease
Mycobacteria Blau’s syndrome (7) Neoplasia
M tuberculosis Hypogammaglobulinaemia Carcinoma
M leprae Histiocytosis X Reticulosis
M kansasii Immune complex disease Pinealoma
M marinum Dysgerminoma
M avian (4) Leucocyte oxidase defects Seminoma
BCG vaccine Chronic granulomatous disease of childhood and adults Reticulum cell sarcoma
Bacteria Malignant nasal granuloma
Brucella
Yersinia (8) Miscellaneous infections
Whipple’s disease
Cat scratch
Lymphogranuloma
Kikuchi
Buruli ulcer

when Th2 seems to override Th1 influences.
There is anergy and apoptosis, which may be
reversed by CD28 agonists.
Immunohistochemistry has revealed a con-
tinuing role for fibronectin, collagen, integrin
receptors, and transforming growth factors in
that slippery road from a healthy granuloma-
tous response to irreversible and unchangeable
fibrosis.
Classification
This large family of granulomatous disorders
comprise infections, vasculitis, immunological
upsets, leucocyte oxidase defect, hypersensitiv-
ity, chemicals, and neoplasia (table 1). DiVer-
ential diagnosis and management demand a
skilful interpretation of clinical findings and
histology5 (table 2).
(1) INFECTIONS
Infections are the commonest causes of dis-
seminated granulomatous disease (table 2).
Some experts regard an infection as the root
cause of all such disorders but that it still
remains undetected in some; over the past dec-
ade advances in molecular diagnostic tech-
niques have allowed identification of causal
organisms that were previously unrecognised.
For instance, cat scratch disease is due to Bar-
tonella henselae and Whipple’s disease due to
Table 2 Histological comparison of various granulomatous disorders
Tropheryma whippeli. Infective causes are sus-
pected but not yet established for sarcoidosis,
Crohn’s disease, primary biliary cirrhosis,
Kikuchi’s disease, Langerhans’ granulomato-
sis, and chronic granulomatous disease of
childhood. The aetiology, course, prognosis,
and treatment of granulomatous infections
have been reviewed elsewhere.6 The present
review draws attention to some which currently
give rise to diagnostic confusion.
Mycobacterial infections
This large family of mycobacteria is responsi-
ble for granulomatous disorders of many
diVerent systems (table 3). The invading
organism is met by a vigorous cell mediated
hypersensitivity reaction involving macro-
phages, Th1 lymphocytes, and their cytokines.
The polymerase chain reaction (PCR) has
uncovered mycobacterial DNA in sarcoid
tissue and mycobacterial RNA has been
extracted from sarcoid spleen by liquid phase
DNA/RNA hybridisation giving rise to false
speculations concerning the aetiology of sar-
coidosis.
Swimming pool (fish tank) mycobacterial
granuloma
Mycobacterium marinum causes swimming pool
(fish tank) granuloma. Although the primary

Schaumann Interstitial cellular Mediastinal

Features Sarcoid granuloma Necrosis bodies inflammation Cavities Vasculitis adenopathy

Sarcoidosis + — +++ ± ±— ± +
Tuberculosis + ++ Caseation ±— ± + ± + (Primary)
Extrinsic allergic alveolitis + (Acute stage) — ± ++ — ++ —
Beryllium disease (chronic) + ± ++ ++ — — —
Wegener’s granulomatosis ± ++ Infarction — ++ Giant cell ++ ++ Rare
Lymphomatoid granulomatosis ± ++ — ++ Immature ± ± Rare
Bronchocentric granulomatosis + + — Eosinophil ± ± Rare
Necrotic sarcoidal granulomatosis + ++ — ++ Mature + ++ ±
Churg-Strauss granulomatosis ++ ++ — ++ Mature — ++ Rare

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Granulomatous disorders 459

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Table 3 Granulomatous mycobacterial infections Beware also of sea urchin granuloma of the
feet in bathers and fishermen stepping on sea
Clinical disorder Common site Mycobacteria
urchins.
Tuberculosis Lung M tuberculosis
Meninges
Skin Buruli ulcer
Intestine Mycobacterium ulcerans is the cause of
Leprosy Skin M leprae chronic, relatively painless, cutaneous Buruli
Tuberculoid Nervous system ulcers. The disease is most prevalent in Africa
Lepromatous Soft tissues
and Australia. The organism causes extensive
Bronchopneumonia Lung M avium complex; M kansasii; undermined ulcers on the extensor surface of
Lymphadenitis Lymph node M xenopi; M simiae;
Osteomyelitis Bone M scrofulaceum; M chelonee; the extremities. The centres of the ulcers are
AIDS Joints M malmoense; M fortuitum necrotic, and the edges are undermined; the
Meninges organisms are usually found at the periphery,
Swimming pool and fish tank Skin M marinum or M balneum where granulation tissue is most extensive.
granuloma Soft tissues While it is relatively easy to diagnose Buruli
Draining lymph nodes
skin ulcers on the basis of clinical features and
Buruli ulcer Skin M ulcerans
Soft tissues
histological findings, microbiological identifi-
cation of the causal mycobacteria may some-
times be quite diYcult, requiring long periods
skin infection may be inconspicuous, the of culture. Newer techniques such as gas phase
draining lymph nodes are extensively involved chromatography are becoming useful for iden-
and caseous. A similar microscopic picture, tification of the acid-fast bacilli in low count
with conspicuous plasma cell infiltration, is subcultures.
associated with granulomas due to other
opportunistic mycobacteria. Fish tank granulo-
Granulomatous mycoses
mas develop in persons with minor abrasions Granulomatous fungal infections mimic sar-
who dip their hands in tropical fish tanks. Usu- coidosis worldwide. It is important to recognise
ally a solitary granuloma, nodule, or pustule or exclude fungi localised to one system or dis-
forms, which may ulcerate or suppurate; but, seminated; in particular, granulomatous fungal
multiple lesions may extend along the line of meningitis needs to be distinguished from sar-
lymphatic vessels. coidosis by all available techniques (table 4).
Biopsy specimens that are cultured on
Löwenstein-Jensen medium at room tempera- Whipple’s disease
ture yield pigmented mycobacterial colonies in George Hoyt Whipple’s single case report
2–4 weeks. The response to treatment is described a 37 year old medical missionary
variable and not dramatic. Antituberculous who presented with fever, polyarthritis, and
drugs, cotrimoxazole, and high doses of mino- steatorrhoea.7 It is a chronic multisystem
cycline have been advocated. granulomatous disorder aVecting middle aged
The development and application of mo- white males, presenting with fever, polyarthri-
lecular techniques such as PCR may in the tis, weight loss, and diarrhoea progressing to
future allow more accurate diagnosis. malabsorption. There may be hepatospleno-
Table 4 Granulomatous mycoses

Fungus Clinical diagnosis Immunopathology Method of diagnosis Treatment

Nocardia sp Actinomycosis Pneumonia Microscopy Penicillin

Actinomyces sp Granuloma Culture Minocycline
Fibrosis
Coccidioides immitis Coccidioidomycosis Bronchopneumonia Culture Amphotericin B
Cavitation CFT Flucytosine
Chronic granuloma ELISA Fluconazole
Tube precipitin
Cryptococcus neoformans Cryptococcosis Pneumonia Microscopy Fluconazole
Infarction Culture Amphotericin B
Abscess Flucytosine
Granuloma fibrosis
Candida sp Candidiasis Abscess Microscopy Nystatin
Monoliasis Necrosis Culture Amphotericin B
Granuloma
Sporothrix schenkii Sporotrichosis Granuloma Microscopy, culture Amphotericin B
Histoplasma capsulatum Histoplasmosis Pneumonia CFT Amphotericin B
Cavitation Microscopy Ketoconazole
Granuloma Radioimmunoassay Rifampicin
Culture
Aspergillus fumigatus Aspergillosis Necrotising granuloma Microscopy Amphotericin B
Culture Itraconazole
Precipitins
Paracoccidioides brasilliense South American blastomycosis Bronchopneumonia Culture Amphotericin B
Pulmonary cavities Sputum Flucytosine
Exudate → granuloma CFT Sulfadiazine
Blastomyces dermatitidis Blastomycosis Microabscess Culture Amphotericin
Pneumonia Itraconazole
Phialophora sp Chromoblastomycosis Cutaneous granuloma Culture Flucytosine
Madurella sp Mycetoma Subcutaneous granuloma Grains in pus Ketoconazole
Itraconazole
Dapsone

CFT = complement fixation test. ELISA = enzyme linked immunosorbent assay.

www.postgradmedj.com
460
megaly and generalised lymphadenopathy. Bi-
opsy of lymph node, liver, or small intestine
reveals foci of PAS staining foamy macro-
phages in all sites. The PAS positive material
within these histiocytes corresponds with lyso-
somes containing bacilliform bodies. Electron
microscopy reveals rod shaped bacilli, termed
Whipple bacilli or T whippelii or Whipple asso-
ciated bacterial organism.8 The nucleic acids
extracted from an endoscopic biopsy specimen
of the proximal small bowel of a patient with
Whipple’s disease has been subjected to nucle-
otide sequencing and amplification by the
PCR. The resulting PCR product from the
bacterial 16S ribosomal DNA was then the
subject of a computer database search for the
rRNA sequences most similar to it. It showed
that Whipple bacilli were most likely to belong
to the family of Gram positive bacteria of the
rhodococcus, streptomyces and arthrobacter
genera, and more weakly related to mycobacte-
ria. PCR primers for T whippeli now provide a
helpful diagnostic technique.9
Cat scratch disease
Cat scratch disease or fever is also known as
benign lymphoreticulosis or regional granulo-
matous lymphadenitis. It only occurs in
humans, especially those who are scratched or
bitten by kittens and then develop regional
lymphadenitis proximal to the site of injury.
Primary involvement is that of the lymph
nodes, which first show lymphoid hyperplasia.
Later, scattered granulomas with central areas
of necrosis coalesce to form abscesses. B hense-
lae is the responsible Gram negative bacillus. It
is identified by PCR hybridisation and indirect
fluorescent antibody assay.
The histopathological features of cat scratch
disease are not diagnostic and may be mistaken
for tularaemia, lymphogranuloma venereum,
syphilis, brucellosis, atypical mycobacterial
infections, fungal infections, and toxoplasmo-
sis. Warthin-Starry silver staining is used to
detect B henselae, which may be present in the
early phase of the disease. A skin test antigen
has been made from lymph node pus. It is
inoculated intradermally, and the degree of
induration and erythema is measured at 48
hours.
The cat scratch antigen skin test is positive in
about 90% of patients who are clinically
suspected of having the disease. This test will
become redundant when techniques for ampli-
fying specific nucleotide sequences with PCR
come into general use. There is no well recog-
nised response to antibiotics, and recovery
usually occurs without treatment.
Kikuchi’s disease
This disorder was described in 1972 by a Japa-
nese pathologist and is characterised by
lymphadenitis showing focal reticulum cell
hyperplasia, nuclear debris, and phagocytosis.9
Clinically there is localised tender cervical
lymphadenopathy with an upper respiratory
prodrome. Most cases occur in women under
the age of 30 years. Kikuchi’s disease occurs
world wide and has been often confused with
toxoplasmosis, cat scratch disease, tuberculo-
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sis, infectious mononucleosis, and non-
Hodgkin’s lymphoma. A viral aetiology is
strongly suspected on the basis of clinical
features, although serological and ultrastruc-
tural studies have not yet identified an
infectious agent.10
(2) VASCULITIS
The family of vasculitic granulomatoses com-
prise Wegener’s granulomatosis, necrotising
sarcoidal granulomatosis, Churg-Strauss syn-
drome, lymphomatoid granulomatosis, polyar-
teritis nodosa, bronchocentric granulomatosis,
giant cell arteritis, and systemic lupus ery-
thematosus. They may occasionally be con-
fused with sarcoidosis and hypersensitivity
pneumonitis (extrinsic allergic alveolitis), so a
careful clinicopathological synthesis is essential
(table 5).
Granulomatous vasculitis is a small group of
systemic disorders of unknown cause and
obscure pathogenesis. It has long been consid-
ered that both humoral and cellular immune
mechanisms are involved, and a cascade of
cytokines may influence their course. The
future management may indeed depend upon
manipulation of this cytokine network.
(3) IMMUNOLOGICAL ABERRATIONS
The causal agent or antigenic insult remains
unrecognised in many granulomatous disor-
ders so they are clumsily lumped together as a
group in which an immunological upset plays a
major part. They are waiting for the cause to be
found or the immune process better under-
stood. Within this category are sarcoidosis, pri-
mary biliary cirrhosis, hepatic granulomatous
disease, Langerhans’ granulomatosis, orofacial
granulomatosis, Peyronie’s disease, Blau’s syn-
drome, hypogammaglobulinaemia, and im-
mune complex disease.
Sarcoidosis
Sarcoidosis is a multisystem disorder of
unknown cause(s) most commonly aVecting
young adults, and frequently presenting with
hilar lymphadenopathy, pulmonary infiltration,
ocular and skin lesions. The diagnosis is estab-
lished most securely when well recognised
clinicoradiographic findings are supported by
histological evidence of widespread epithelioid
granuomas in more than one system. Multisys-
tem sarcoidosis must be diVerentiated from
local sarcoid tissue reactions. There is imbal-
ance of CDT4:T8 subsets, an influx of Th1
helper cells to sites of activity, hyperactivity of
B cells, and circulation of immune complexes.
Markers of activity include raised levels of
serum angiotensin converting enzyme and
monocyte chemoattractant protein-1; abnor-
mal calcium metabolism; a positive Kveim-
Siltzbach skin test; intrathoracic uptake of
radioactive gallium; and abnormal fluorescein
angiography.
The course and prognosis correlate with the
mode of onset. An acute onset usually heralds
a self limited course of spontaneous resolution
whereas an insidious onset may be followed by
relentless progressive fibrosis. Corticosteroids
relieve symptoms, suppress the formation of
Granulomatous disorders 461

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granulomas (including Kveim-Siltlzbach

Only when associated with

lupus pernio and SURT
granulomas), and normalise both levels of

Insignificant symptoms
serum angiotensin converting enzyme and the
uptake of gallium. A synthesis of clinical

Nephrocalcinosis

Inconspicuous
Inconspicuous
features, radiology, histology, biochemical

Raised SACE

Azathioprine
Infiltration
Sarcoidosis changes, and immunological abnormalities

30 and 40

Steroids
Always
helps to distinguish it from non-specific local

Good
Same sarcoid tissue reactions.

+
−
+

+
+

+
Tumour necrosis factor alpha (TNF-á) is a
proinflammatory cytokine widely recognised
and implicated in inflammatory disorders
No asthma

Dyspnoea
including sarcoidosis. It is inhibited by tumour
Pleurisy
Cough
Same

necrosis factor receptor (TNF-R) which is rec-

Hypersensitivity to aspergillus
60
Bronchocentric granulomatosis

+
−

−
+
−

+
−

−
ognised in two forms p55 (CD120a) and p75

±
Particularly is upper lobes (CD1206) receptors. This TNF-TNF-R bal-
Bronchial obstruction

Pulmonary fibrosis ance in favour of inhibition may represent a

homoeostatic mechanism which protects the

Corticosteroids
Bronchiectasis

patient from excessive TNF production in sar-

Eosinophilia

Eosinophilia

ANCA: antineutrophil cytoplasm autoantibody; ESR = erythrocyte sedimentation rate; SACE = serum angiotensin converting enzyme; SURT = sarcoidosis upper respiratory tract.
coidosis. TNF-R p55 is increased in stage I
Asthma
Asthma

more than stage II/III sarcoidosis, suggesting

Good
Same

that homoeostasis is responsible for a more

30

+
−

−
+
−

+
−

±
benign outcome at this early stage of
sarcoidosis.11
Necrotising sarcoid
granulomato sis

Crohn’s disease
Azathioprine
Prominent
30 and 40

The commonest cause of granulomatous in-

Steroids
Pleurisy
Malaise

Always
Cough

Good flammation in the gastrointestinal tract is

Same

Fever

Rare

Crohn’s disease. This reaction seems to centre

++
+
+
−

−
−
−

−
−

on the blood vessels of the intestinal wall caus-

ing multifocal gastrointestinal infarction.
There may be associated lung changes, includ-
Churg-Strauss

ing pulmonary vasculitis, granulomatous inter-

Azathioprine
Eosinophilia
Pneumonia

Infiltration

Prominent
Infrequent
Bronchitis

stitial lymphocytic infiltration, alveolitis, and

syndrome

Steroids
Asthma

Always

interstitial fibrosis. Alveolar macrophages may

Same

Poor
Rare

show an increased spontaneous superoxide

50

−
−
+

−
−

anion production. An increase in CD4 cells is

Lymphomatoid granulomatosis

found in bronchoalveolar fluid and even in

M slightly more frequent

sputum. Serum antibody increases include

antireticulin antibody, antisaccharomyces cer-
Cyclophosphamide

evisiae antibody (ASCA), and p-antineutrophil

Renal vasculitis

cytoplasmic antibody (ANCA). There is con-

Haemoptysis

Asathioprine
Prominent
Arthralgia
Dyspnoea

cordance between ASCA and p-ANCA. ASCA

Very rare
Always
Cough

occurs in up to 60% of patients, particularly

30–50

Poor

with familial Crohn’s disease; and ASCA is

+
+

−
−
+

−
−

evident in 20% of first degree relatives.5 12 13

Primary biliary cirrhosis (PBC)

PBC is a chronic non-suppurative destructive
Limited

Equal

cholangitis14 in which epithelioid granulomas

DiVerential diagnosis of pulmonary granulomatous vasculitis

++
50

+
+

−
+

−
−

−
±

are in close association with bile ducts. It

Prominent and resemble infarcts

predominates in women of the reproductive

Glomerulonephritis in 85%

years of age and it is distinguished by the pres-

Wegener’s granulomatosis

ence of serum mitochondrial antibodies. It is

classified as an autoimmune disorder and over-
Cyclophosphamide

laps with other autoimmune disorders includ-

+ Present, ++ prominent, − absent, ± inconspicuous.
Rhinorrhoea

ing Sjogren’s syndrome, rheumatoid arthritis,

the calcinosis Raynaud oesophagus sclero-
Guarded
Epistaxis
Sinusitis

Steroids
ANCA
M>F
Classic

derma telangiectasia (CREST) syndrome, scle-

ESR
++

++
50

roderma, and systemic lupus erythematosus.

+

+
+

+
±

Cholangiocyte apoptosis is responsible for

bile duct destruction due to aberrant expres-
Ulcerated nose and nasal septum

sion of the major autoantigen, the E2 subunit

of the pyruvate dehydrogenase complex. There
Central nervous system

is some evidence that PBC with high titres of

Decade of incidence

antinuclear antibodies progress slower and

Chest radiography

Hilar adenopathy

result in a better prognosis than those with low

Characteristics

titre or negative antinuclear antibodies.

Cavitation
Presentation

Granulomas
Saddle nose

Skin lesions
Opacities

Treatment

Prognosis

PBC histology may be granulomatous or

Vasculitis
Necrosis
Kidneys

Cardiac
Features
Table 5

Allergy
Ocular

alternatively eosinophilic. Could this be due to

F:M

the predominant influence of either the Th1

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462
cytokine cascade producing granulomas or the
Th2 cascade causing an eosinophilic response?
The aetiology of PBC remains unknown.
There are similarities between Escherichia coli
and mitochondrial components; cross reactiv-
ity between bile duct mitochondria and bacte-
ria is a possibility. An increased incidence of
Gram negative urinary tract infections is
recognised in PBC. It has been likened to the
chronic graft-versus-host rejection with similar
structural change in the bile ducts, lacrimal and
pancreatic ducts, which have a high concentra-
tion of HLA class II antigens on the epithelial
surface.
A diVerential diagnosis of some hepatic
granulomatous disorders is appended (table 6).
Langerhans’ cell granulomatosis
The term Langerhans’ cell granulomatosis
refers to proliferative disorders of histiocytes,
previously referred to as histiocytosis X. It
encompasses a group of disorders of unknown
aetiology characterised by granulomatous infil-
tration of the lungs, bone, skin, lymph nodes,
and brain.5 15 The clinical conditions have been
known by several names, based on the type of
presentation, sites of involvement, rate of
progression, and degree of associated immune
dysfunction. They include eosinophilic granu-
loma, Letterer-Siwe disease, and Hand-
Schüller-Christian disease. They are diVerent
expressions of the same basic disorder, in
which the proliferation of Langerhans’ cells
results from disturbances in immunoregula-
tion.
Langerhans’ histiocytes are bone marrow
derived monocyte macrophage cells; they
include Langerhans’ epidermal cells, KupVer’s
cells in the liver, osteoclasts, and alveolar mac-
rophages. They are human leucocyte antigen
DR positive functioning macrophages that
present antigen to T cells and play a part in cell
mediated immunity. Unlike histiocytes, Lang-
erhans’ cells can be stained immunohisto-
chemically for S-100 protein and OKT-6.
Lung biopsy reveals a mixed cellular exu-
date, foam cells, eosinophils, and characteristic
Table 6 DiVerential diagnosis of some diseases with
hepatic granulomas
Disease Diagnostic aids
Sarcoidosis Chest radiograph; Kveim; SACE
Bronchoalveolar lavage
Tuberculosis Tuberculin skin test
Bronchoalveolarlavage
Acid-fast staining
Isolation organism
Brucellosis Blood culture
Agglutinin titre
Berylliosis Industrial exposure
Chest radiograph
Syphilis Treponema test
Leprosy Race; lepromin skin test
Histoplasmosis Complement fixation test
Chest radiograph
Infectious Blood film, monospot, IgM
mononucleosis Epstein-Barr antibodies
AIDS Poorly formed granulomas
Acid-fast and fungal stains
HIV test
Primary biliary Mitochondrial antibody
cirrhosis
Lymphomas Chest radiograph; lymph node biopsy
Computed tomography
SACE = serum angiotensin converting enzyme.
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X bodies (Birbeck granules) in macrophages.
Langerhans’ or X bodies are an ultrastructural
feature in 90% of patients. They are identical to
the granules in Langerhans’ epidermal cells
and consist of intracytoplasmic rod, plate, or
cup-like pentalaminar structures. The presence
of these tennis racket shaped ultrastructural
Birbeck granules is diagnostic of the disorder.
They have surface adenosine triphosphate
activity identifiable by gold fluorescence. These
diagnostic cells are readily found by broncho-
alveolar lavage, and this technique may make
lung biopsy unnecessary. It may also be a likely
means of detecting a possible causal agent in
the future.
Orofacial granulomatosis (Melkersson-Rosenthal
syndrome)
This is a rare granulomatous disorder of the
mouth and adjacent tissues, involving the oral
mucosa, gum, lips, tongue, pharynx, eyelids,
and skin of the face.
Melkersson described an association be-
tween facial oedema and facial paralysis.16
Rosenthal added the features of lingua plicata
or scrotal tongue.17 Other clinical features
include granulomatous cheilitis, oedema of the
gums and scalp, salivary gland dysfunction,
granulomatous blepharitis, trigeminal neural-
gia, Raynaud’s phenomenon, and even chronic
hypertrophic granulomatous vulvitis.18 19 Pa-
tients with this disorder do not have chest
radiography changes, nor uveitis; and the
Kveim-Siltzbach skin test is negative. This rare
disorder may be immunologically mediated for
the T cell receptor B (TCRVB) repertoire is
restricted.20 This is evident in oral mucosal
lymphocytes, and it is associated with a local T
cell clonal expansion. These features suggest a
delayed type reaction in response to an
unknown antigen. Local cytokine release may
be responsible for the granulomatous reaction.
Blau’s syndrome
Edward Blau is a Wisconsin paediatrician who
described a multisystem granulomatous dis-
ease of the skin, eyes and joints, resembling
childhood sarcoidosis.21 The histology may be
indistinguishable so paediatricians should be
aware of significant diVerences between the
two disorders. The most frequent manifesta-
tion is swelling of the wrists, fingers, ankles, and
elbows in the first decade of life. Because of the
granulomatous histology of synovial tissue, it
may be misdiagnosed as tuberculosis of bone.
There may be progression of flexion contrac-
tures of joints (campodactyly) due to post-
inflammatory fibrotic scarring at insertion
points of finger and toe flexor tendons. There is
a granulomatous red papular eruption of the
skin with a butterfly distribution on the face. It
coincides with exacerbations of the granuloma-
tous iritis.
Blau’s syndrome is a multisystem disorder in
which there is no lung involvement; this may be
an important diVerence from other granuloma-
tous disorders.
The granulomas of Blau’s syndrome are
indistinguishable from those of sarcoidosis by
light microscopy or by immunocytochemistry.
Granulomatous disorders
However asteroid, Schaumann and conchoid
bodies, organisms, calcification and crystalline
inclusions, necrosis and fibrin deposition are
absent.
Granulomatous hypogammaglobulinaemia
On rare occasions, one wonders whether the
patient has hypogammaglobulinaemia or sar-
coidosis or both. Confusion arises since both
conditions may present with multisystem
granulomas, hypersplenism, and poor cellular
immunity. The hypogammaglobulinaemia may
be selective IgA deficiency or a more wide-
spread deficiency of IgA, IgG, and IgM. There
is bedside clinical evidence of loss of both B
and T lymphocyte function, which is also
evident by in vitro lymphoproliferative assays.
(4) LEUCOCYTE OXIDASE DEFECTS
Killing of bacteria depends on a burst of respira-
tory enzyme activity which leads to the produc-
tion of hydrogen peroxide and superoxide in
phagocytes. Neutrophils in chronic granuloma-
tous disease of childhood (CGDC) are unable to
kill some ingested bacteria because they are
deficient in enzymes needed for this superoxide
respiratory burst. These defective enzymes may
be nicotinamide adenine dinucleotide phos-
phate (NADPH) oxidase, myeloperoxidase,
cytochrome B, pyruvate kinase, glucose-6-
phosphate dehydrogenase, or the lack of lys-
ozyme or lactoferrin, each perhaps contributing
a diVerent clinical profile. The classical X linked
disorder occurs in boys aged about 5 years, pre-
senting with hepatosplenomegaly, generalised
lymphadenopathy, weeping granulomatous skin
lesions, and diVuse miliary lung infiltration. The
history is of multisystem sarcoid granulomas.
There is more than one X linked form and also
more than one autosomal recessive variety, for
there is more than one mechanism for initiating
oxidative metabolism.22 Patients with CGDC
suVer from infections with catalase-producing
staphylococci and enterobacteria. Organisms
that lack catalase supply the neutrophil with the
hydrogen peroxide for their own destruction.
Thus catalase negative organisms, such as pneu-
mococci or streptococci, present no problem to
these patients. Neutrophil leucocytes of normal
patients with bacterial infections reduce nitro-
blue tetrazolium from colourless to form blue-
black formazan granules in the cytoplasm. This
fails to occur in the leucocytes of CGDC
children or in the mothers of the X linked vari-
ety. The X linked variety is due to mutations in
the gene for the gp 120-phox subunit of the
phagocyte cytochrome b, an essential compo-
nent of superoxide-generating NADPH oxidase.
Most patients have undetectable levels of
cytochrome b and no phagocyte NADPH
oxidase activity. This gives rise to life threatening
bacterial and fungal infections in infancy. Some
patients have a milder course because they retain
some cytochrome NADPH oxidase activity.
IFN-ã has proved helpful in enhancing host
defences and thereby reducing the incidence of
life threatening infections, particularly those
infections characterised by persistence in mac-
rophages (toxoplasmosis, leishmaniasis, and
mycobacteriosis).9
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Thrasher et al used an adenovirus vector
expressing p47-phox to transduce patients’
defective monocytes.23 Nitroblue tetrazolium
staining indicated that NADPH oxidase activ-
ity was restored to those cells. This technique
oVers a rapid means for molecular diagnosis
and points to a therapeutic future of gene
transduction.
Chronic granulomatous disease in adults (CGD)
Chronic granulomatous disease is being recog-
nised more commonly in adults. Although it is
still rare it should be excluded in adults with
unexplained granulomas or infections.24 Anti-
biotic prophylaxis and the use of IFN-ã has
allowed children, mostly with reduced gp91-
phox (X91-CGD), to present for the first time
in young adult life. The NBT is insuYcient as
a screening test for it may give values close to
normal in adults. It should be complemented
by chemoluminescence or cytochrome b re-
duction. This is important because of the ben-
efits of earlier diagnosis and treatment, infec-
tion prophylaxis, and genetic counselling.
(5) HYPERSENSITIVITY PNEUMONITIS (EXTRINSIC
ALLERGIC ALVEOLITIS)
Repeated inhalation of various antigens may
provoke a granulomatous inflammatory re-
sponse in the bronchoalveolar spaces and
interstitium giving rise to a family of pulmo-
nary disorders termed hypersensitivity pneu-
monitis or extrinsic allergic alveolitis. The best
recognised members of the family are farmers’
lung, pigeon breeders’ lung, and humidifier
fever. The clinical picture may be acute and
explosive, subacute and insidious, or chronic
and protracted; cough and dyspnoea on
exertion, fatigue, and weight loss are common.
The end stage is characterised by irreversible
restrictive lung function and cardiac failure.
Pathogenesis involves a complex interplay of
circulating immune complexes, immediate
hypersensitivity, and exuberant cell mediated
immunity. The diagnosis is established by a
history of occupational exposure; suggestive
clinical and radiological changes; and demon-
stration of precipitating serum antibodies. Mid
to late inspiratory crackles and the absence of
finger clubbing are notable features. An
increase in CD8+ T cells in bronchoalveolar
fluid is also noteworthy.
(6) CHEMICALS
There are four granuloma forming chemicals:
beryllium, zirconium, silica, and talc.5 13
Beryllium disease mainly aVects the lungs
following inhalation of soluble, finely particu-
late beryllium and its salts. Direct implantation
may also give rise to skin ulcers and nodules.
Pulmonary disease may be acute or chronic
(CBD); the former is a chemical pneumonitis
after massive exposure to fumes whereas CBD
is a chronic granulomatous disorder. It is due
to occupational exposure in a variety of indus-
trial processes, alloy workers, ceramic workers,
and in space and atomic engineers. The respi-
ratory symptoms are in keeping with diVuse
and nodular fibrosis of the lungs, with pleural
thickening and late cystic changes. The granu-
464
loma contains a variety of inclusion bodies,
Schaumann and asteroid; they are end prod-
ucts of the actively secreting epithelioid cells.
Diagnostic criteria include history of exposure;
consistent clinicoradiological features, granulo-
matous histology, and tissue analysis for beryl-
lium.
Zirconium
This chemical was recognised as a cause of
deodorant axillary granulomas in sensitised
individuals. A 1:10 000 solution of zirconium
chloride or nitrate inoculated intradermally
produced a palpable nodule, which, on biopsy,
revealed sarcoid tissue. This was specific for
zirconium hypersensitivity. This skin test is
very similar to the Kveim-Siltzbach skin test for
sarcoidosis. Zirconium is no longer in deodor-
ants so these axillary granulomas are no longer
seen. However it is of some academic interest
that there are four granulomatous disorders in
which skin tests behave in this peculiar fashion,
mimicking the Kveim-Siltzbach test. The other
two were the beryllium patch test and the Mit-
suda skin test in lepromatous leprosy.
Silicosis
Inhalation of pure silica may be followed by
dense nodular and rarely diVuse pulmonary
fibrosis. The silica granuloma is readily identi-
fied by the presence of crystalline birefringent
crystals in macrophages with foreign body
rather than Langhans-type giant cells.
Pulmonary talc granulomatosis
This is due to the inhalation of talc in the form
of talcum powder or by prolonged repeated
intravenous administration of pentazocine
(75% talc).
(7) NEOPLASIA
There is often a granulomatous component in
malignant disease. Sarcoid granulomas may be
found in various tumours and in their draining
lymph nodes, particularly those draining carci-
noma of the lung, stomach, and uterus. They
may also be found in tumours that have been
treated by radiotherapy or chemotherapy, since
treatment may produce a granulomagenic sub-
stance which spreads to draining lymph nodes.
There is diagnostic confusion between sar-
coidosis and Hodgkin’s disease, in which multi-
system granulomas are also observed. The dif-
ficulty usually arises in the interpretation of
small specimens of aspiration liver biopsies, or
the occasional patient in whom the spleen is
replaced by sarcoid tissue obliterating tumour
tissue. Intrathoracic Hodgkin’s disease most
frequently aVects the upper mediastinum
rather than hilar lymph nodes, and it is
predominantly unilateral. The hilar nodes tend
to fuse with the right cardiac border whereas in
sarcoidosis they stand away from the cardiac
border. Both disorders show depression of cell
mediated immunity. In Hodgkin’s disease, the
Kveim-Siltzbach test is negative and serum
angiotensin converting enzyme levels are raised
in only about 10% of patients, compared with
60% in sarcoidosis.
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(8) MISCELLANEOUS
Granulomatous angiitis
Granulomatous angiitis is a multifocal chronic
inflammatory disorder in which magnetic reso-
nance imaging may show multiple discrete
granulomas. The initial diagnosis may suggest
an infection, such as tuberculosis or toxoplas-
mosis, or alternatively intravascular lympho-
matosis.
Granuloma annulare
These skin lesions may be single, multiple, or
disseminated with flat centre and a well deline-
ated edge. The histology is of a necrobiotic area
with palisading granulomas in giant cells. A
similar histological reaction may be seen in
rheumatoid disease and with a ruptured
sebaceous cyst.
Actinic granuloma
This disfiguring condition is a granulomatous
reaction to excessive sun exposure. There is
debate whether it is a distinct clinicopathologi-
cal entity or a variant of granuloma annulare or
multiforme and necrobiosis lipoidica. Treat-
ment with isotretinoin has prevented develop-
ment of new granulomas and produced almost
complete resolution of established lesions.
Granulomatous rosacea
Rosacea has been described as the curse of the
Celts.25 It is commoner in women, aged 30 to
50 years. There is a background diathesis of
flushing and blushing, upon which develops
erythema, papules, pustules, telangiectasia,
furuncles on the face, neck and v-shaped area
of the chest. Granulomatous or lupoid rosacea
nodules may also involve the lower eyelids.
Histology reveals perifollicular and perivascu-
lar granulomas; it needs to be distinguished
from micronodular sarcoidosis, particularly
since both conditions may be associated with
iritis and conjunctivitis. Minidose isotretinoin,
2.5 mg to 5 mg daily, oral tetracycline, or met-
ronidazole may be helpful for lupoid rosacea.
Other
Do not be surprised if the histological report of
a removed sebaceous cyst indicates a granu-
loma. The same granulomatous reaction oc-
curs in chalazion, dermoid, panniculitis, sea
urchin spine injury, tattoos, or malakoplakia. It
indicates a vigorous macrophage Th1 reaction
to the antigenic insult, involving cytokines and
other biological mediators (fig 1). It indicates a
good defence and a satisfactory outcome
against the antigenic aggression.
1 James DG. What makes granulomas tick? Thorax
1991;46:734–6.
2 James DG.Granuloma formation signifies a Th1 cell profile.
Sarcoidosis 1995;12:1–3.
3 Roman J, Leon YJ, Gal A, et al. Distribution of extracellular
matrices, matrix receptors, and transforming growth
factor-1 in human and experimental living granulomatous
inflammation. Am J Med Sci 1995;309:124–33.
4 Reiser H, Stadecker MJ. Costimulatory B7 molecules in the
pathogenesis of infectious and autoimmune diseases. N Engl
J Med 1996;335:1369–77.
5 James DG, Zumla A. The granulomatous disorders.
Cambridge: Cambridge University Press, 1999.
6 Zumla A, James DG. Granulomatous infections: etiology
and classification. Clin Infect Dis 1996;23:146–58.
7 Whipple GH. A hitherto undescribed disease characterised
anatomically by deposits of fat and fatty acids in the intesti-
nal and mesenteric lymphatic tissues. Johns Hopkins Hospital
Bulletin 1907;18:382–91.
Granulomatous disorders
8 Spapen HDM, Segers O, DeWit N. Electron microscopic
detection of Whipple’s bacillus in sarcoidlike periodic acid-
SchiV-negative granulomas. Dig Dis Sci 1989;34:640–3.
9 Kikuchi M. Lymphadenitis showing focal reticulum cell
hyperplasia with nuclear debris and phagocytosis. Nippon
Ketsueki Gakkai Zassi 1972;35:378–80.
10 Kuo TT. Kikuchi’s disease (histiocytic necrotising lymphad-
enitis). A clinicopathological study of 79 cases with an
analysis of histologic subtypes, immunohistology, and DNA
ploidy. Am J Surg Pathol 1995;7:798–809.
11 Armstrong L, Foley NM, Millar AB.Inter-relationship
between tumour necrosis factor-alpha (TNF-á) and soluble
receptors in pulmonary sarcoidosis. Thorax 1999;54:524–
30.
12 Vermeire S, Peeters M, Joossens S, et al. The value of
anti-saccharomyces cerevisial antibodies (ASCA) as clinical
marker in Crohn’s disease (CD). Gastroenterology 1999;116:
abstr 3647.
13 James DG, Jones Williams W. Sarcoidosis and other
granulomatous disorders. Philadelphia: WB Saunders, 1985.
14 Sherlock S, Dooley J. Diseases of the liver and biliary system.
10th Ed. Oxford: Blackwell, 1997: 461.
15 Hance AJ, Candranel J, Soler P, et al. Pulmonary and extra-
pulmonary Langerhans’ cell granulomatosis (histiocytosis
X). Semin Respir Med 1988;9:349–68.
16 Melkersson E. U fall au recidiverande facialispares. Hygiea
1928;90:737–41.
www.postgradmedj.com
465
Postgrad Med J: first published as 10.1136/pmj.76.898.457 on 1 August 2000. Downloaded from http://pmj.bmj.com/ on December 17, 2020 by guest. Protected by copyright.
17 Rosenthal C. Facialislahmung und lingua plicata. Z Neurol
Psychol 1930;131:475–501.
18 Wiesenfeld D, Ferguson MM, Mitchell DN, et al. Oro-facial
granulomatoses. A clinical and pathological analysis. Q J
Med 1985;54:101–13.
19 Larsson E, Westmark P. Chronic hypertrophic vulvitis—a
condition with similarities to cheilitis granulomatosa.
(Melkersson-Rosenthal syndrome). Acta Derm Venerol
(Stockh) 1978;58:92–3.
20 Lim SH, Stephens P, Cao QK, et al. Molecular analysis of T
cell receptor variability in a patient with orofacial granulo-
matosis. Gut 1997;40:683–6.
21 Blau EB. Familial granulomatous arthritis, iritis and rash. J
Pediatr 1985;5:689–93.
22 Curnette JT. Chronic granulomatous disease: the solving of
a clinical riddle at the molecular level. Clin Immunol Immun-
opathol 1993;67:S2–15.
23 Thrasher AJ, Casimir CM, Kinnon C, et al. Gene transfer to
primary chronic granulomatous disease monocytes. Lancet
1995;346:92–3.
24 Schapiro BL, Newburger PE, Klempner MS, et al. Chronic
granulomatous disease presenting in a 69 year old man. N
Engl J Med 1991;325:1786–90.
25 Jansen T, Plewig G. Rosacea: classification and treatment. J
R Soc Med 1997;90:144–50.